Isoliquiritigenin inhibits the proliferation of human renal carcinoma Caki cells through the ROS-mediated regulation of the Jak2/STAT3 pathway.

Abstract

Isoliquiritigenin (ISL) is a flavonoid with chalcone structure that has been noted in licorice and shallot, which are generally used in traditional Chinese medicine. ISL has demonstrated various pharmacological effects including antioxidant, anti-inflammatory and antitumor activity. However, the molecular mechanisms underlying the anticancer effects of ISL remain poorly understood. The present study revealed that ISL significantly decreased viability and induced apoptosis in human renal carcinoma Caki cells. The ISL-induced apoptosis was associated with the cleavage of caspase-9,-7and-3, and that of PARP. Moreover, ISL increased the expression of pro-apoptotic protein Bax and diminished the expression of anti-apoptotic protein Bcl-2, and Bcl-xl, thereby increasing cytochromec release. Treatment of cells with ISL also induced the expression of p53 through downregulation of murine double minute2 (Mdm2). Furthermore, ISL generated reactive oxygen species (ROS), and pretreatment with ROS scavenger N-acetyl cysteine (NAC) and NADPH oxidase inhibitor diphenyleneiodonium abrogated the ISL-induced apoptosis. One of the key oncogenic signaling pathways is mediated through signal transducer and activator of transcription3 (STAT3), which promotes abnormal cell proliferation. Incubation of cells with ISL markedly diminished phosphorylation and DNA binding activity of STAT3, and reduced expression of STAT3 responsive gene products, such as cyclinD1andD2. ISL also attenuated constitutive phosphorylation of upstream kinase, Janus-activated kinase2 (Jak2). Pretreatment with NAC abrogated the inhibitory effect of ISL on activation of STAT3 and blocked the cleavage of caspase-9,-7and-3, and that of PARP in Caki cells. Taken together, the present study provides the first report that ISL induces apoptosis in Caki cells via generation of ROS, which causes induction of p53 and inhibition of the STAT3 signaling pathway.